Structural Contributions to Autocatalysis and Asymmetric Amplification in the Soai Reaction

Abstract

Diisopropylzinc alkylation of pyrimidine aldehydesthe Soai reaction, with its astonishing attribute of amplifying asymmetric auto­catalysisoccupies a unique position in organic chemistry and stands as an eminent challenge for mechanistic elucidation. A new paradigm of “mixed catalyst–substrate” experiments with pyrimidine and pyridine systems allows a disconnection of catalysis from auto­catalysis, providing insights into the role played by reactant and alkoxide structure. The alkynyl substituent favorably tunes catalyst solubility, aggregation, and conformation while modulating substrate reactivity and selectivity. The alkyl groups and the hetero­aromatic core play further complementary roles in catalyst aggregation and substrate binding. In the study of these structure–activity relationships, novel pyridine substrates demonstrating amplifying auto­catalysis were identified. Comparison of three auto­catalytic systems representing a continuum of nitrogen Lewis basicity strength suggests how the strength of N–Zn binding events is a predominant contributor toward the rate of auto­catalytic progression.

One Soai reaction, two mechanisms?

“…It is only in 2020 that the groups of Scott Denmark 34,35 and Oliver Trapp 36 have come each with a conclusive proposal for the mechanism behind the Soai reaction, based on extensive experimental studies supplemented by kinetic modelling or Density Functional Theory (DFT) calculations. As both studies result into seemingly contradictory conclusions -at least on first sight -the present author wishes to provide some food for thought by comparing and discussing these two proposals.…”

“…A closer look reveals that both proposals might be complementary instead of contradictory, leading to far-reaching implications for the fundamental understanding of asymmetry-amplifying autocatalysis in general. This paper uses a nomenclature derived from Denmark's notation: 35 Pm and Py refer to pyrimidyl-and pyridylaldehydes, respectively; PmII and PyII to the respective chiral zinc alkoxides resulting from ZniPr 2 addition. Lower-case prefixes indicate the substituents para to the aldehyde or alcohol moiety, e.g.…”

Absolute Asymmetric Catalysis, from Concept to Experiment: A Narrative

“…11 A quarter of a century later, the Soai reaction (Scheme 1) is still described as 'the only example of an autocatalytic, non-equilibrium, irreversible chemical transformation capable of robust chemical amplification'. 26…”

“…Although it can be shown that the simple Frank model (irreversible enantioselective catalysis coupled to a mutual inhibition step between opposite enantiomers) can reproduce the most important experimental features of the Soai reaction, 25,34 more than twenty years after its discovery the precise details of the essential network of coupled reactions involved in its mechanism are still far from being unambiguously established, and the output of both experimental and theoretical mechanistic investigations continues unabated. 26,35 In the past two decades, perhaps the most important finding has been that the actual autocatalysts are not the monomeric zinc alkoxides 3, but the corresponding homochiral tetramers, 36 and that the heterochiral meso tetramer is not catalytically competent. Thus, although the most complete mechanistic model involves 18 different chemical species and 12 independent parameters (6 rate constants, 3 equilibrium constants and 3 stereoselectivity parameters), 37 the basic features of the Nelson-Kondepudi-Frank model can be easily identified within the reaction Account Synlett network (Scheme 3; compare with Figure 2A) and provide a strong basis for the understanding of the SMSB nature of this reaction as performed in a closed vessel.…”

“…In effect, barring some non-productive off-cycle aggregation-deaggregation equilibria, the reaction network proposed by Micheau, Buhse et al, 37 that integrates the most recent results of kinetic and structural with theoretical results of high-level DFYT calculations, can be analyzed as consisting of: (a) the direct nonenantioselective formation of zinc alkoxides 3 from 1 and diisopropylzinc (slow, essentially irreversible); (b) a series of relatively fast, reversible aggregation/deaggregation reactions that lead to the formation of the actual catalytic homochiral tetrameric species; (c) a couple of two-step asymmetric pseudo-autocatalytic steps (reversible coordination of diisopropylzinc with the tetramer, followed by irreversible, highly enantioselective addition to 1); and (d), essentially irreversible formation of an achiral meso-tetramer (more than 2 kcal/mol more stable than the homochiral catalytic tetramer), 26 that is therefore catalytically inactive. This last reaction plays the role of mutual inhibition in a Frank-like network.…”